The following discussion of the background is merely provided to aid the reader in understanding the present disclosure and is not admitted to describe or constitute prior art.
Ewing's sarcoma is an aggressive and highly metastatic malignancy. It arises in and around the bones of the extremities and central skeleton, but may also arise in the soft tissues. Ewing's sarcoma primarily affects children and young adults, predominantly those of European descent, with the highest rates of development occurring in white male adolescents.
Cells of Ewing's sarcoma appear as small, round, undifferentiated blue cells, and thus belongs to a class of tumors with a similar histologic appearance which includes rhabdomyosarcoma, neuroblastoma, and lymphoma. However, the cellular origin of Ewing's sarcoma is unknown. Most cases of Ewing's sarcoma emanate via a recurrent chromosomal translocation that encodes for the EWS/FLI fusion protein. See Delattre, O., et al., Nature, 359, 162-165 (1992). The FLI portion contains an ETS family DNA-binding domain while the EWS portion functions as a strong transcriptional activation domain. Accordingly, EWS/FLI is an aberrant transcription factor that dysregulates genes involved in tumor development. See May, W. A., et al., Proc Natl Acad Sci USA, 90, 5752-5756 (1993a); May, W. A., et al., Mol Cell Biol, 13, 7393-7398 (1993b). A variety of studies have identified a large number of EWS/FLI-regulated genes. See, e.g., Prieur, A., et al., Mol Cell Biol, 24, 7275-7283 (2004). However, specific genes involved in the proliferation of Ewing's sarcoma oncogenesis have yet to be elucidated.
Glutathione S-transferases (“GSTs”) are detoxification enzymes which inactivate a variety of endogenous and exogenous reactive compounds by conjugation to glutathione. At present, eight distinct classes (alpha, kappa, mu, omega, sigma, theta, pi, and zeta) of soluble and six membrane-bound GSTs have been identified. GSTM4 belongs to the mu class of soluble forms. See Comstock, K. E., et al., J Biol Chem, 268, 16958-16965 (1993); Comstock, K. E., et al., Arch Biochem Biophys, 311, 487-495 (1994).